The invention is a process for making 5-substituted-1H-tetrazoles from nitriles using a Lewis acid and an azide or a preformed metal azide complex. The process is exceptionally useful for synthesizing sterically hindered 5-substituted-1H-tetrazoles.
The classical method (W. G. Finnegan et al., J. Am. Chem. Soc. 1958, 80, 3908) of synthesizing tetrazoles from nitriles uses ammonium chloride/sodium azide/N,N-dimethylformamide, but this fails to react, in acceptable yield and purity, on sterically hindered nitriles. Hindered 5-substituted-1H-tetrazoles cannot be synthesized in acceptable yield or purity using ammonium chloride/sodium azide/N,N-dimethylformamide. Exothermic decomposition of the reaction products occurs yielding volatile products with a large heat of decomposition, thereby making the reaction unsafe.
The method of J. V. Duncia (J. Org. Chem., 1991, 56, 2395) uses trimethyltin or tributyltin azide to produce tetrazoles in good yield. Trimethyltin azide must be prepared in advance and tributyltin azide is prepared in situ. When working with large scale preparations, the tin by-products are difficult to remove, thus requiring extensive and tedious chromatography. The use of anhydrous hydrogen chloride gas, used to cleave the tin-tetrazole bond, is not desired when working with large quantities.
The sterically hindered 5-substituted tetrazoles of the present invention are useful as intermediates in a variety of compounds, particularly as intermedaites in preparing biphenyl-tetrazole angiotensin II receptor antagonists useful as cardiovascular agents. See, for example European Patent Application No. EP-253310, EP-324377, and EP-497150.